Conventional proteomics methods were used to generate draft human proteomes.

Credit: Nature

WORK FLOW

Conventional proteomics methods were used to generate draft human proteomes.

Credit: Nature

A map of the human genome has existed for more than a decade. A similar map of the proteome—the complete catalog of proteins encoded by the genome—has not been assembled, although many of the pieces have been available.

The wait is now over. Two independent teams have assembled draft maps of the human proteome that they will make publicly available.

One team, led by Akhilesh Pandey of Johns Hopkins University School of Medicine in collaboration with the Institute of Bioinformatics in Bangalore, India, performed high-resolution mass spectrometric analysis of 30 normal human tissues (Nature 2014, DOI: 10.1038/nature13302). They identified proteins encoded by 17,294 genes.

Another team, led by Bernhard Kuster of Technical University of Munich, in Germany, combined new mass spectrometric analyses of 60 tissues, 13 body fluids, and 147 cell lines with data already available in the literature (Nature 2014, DOI: 10.1038/nature13319). They found evidence for 18,097 proteins.

The proteins the teams found account for 80–90% of those predicted to exist. The biggest gap is in the class of proteins known as G-protein coupled receptors, or GPCRs. Many of these missing proteins are thought to be involved in taste and smell perception. Many of them, Kuster says, may be evolutionary remnants that are no longer needed and thus not actually produced.

Both studies found some surprises. For example, Pandey’s group found several proteins that are coded by previously assumed noncoding RNAs. “Clearly at least a subset of these noncoding RNAs are translated,” Pandey says. Kuster’s analysis likewise traced some proteins back to sequences thought to be noncoding RNAs.

Kuster’s study identified a “core proteome” that consists of a large number of proteins that are found in all tissues. That finding led to another surprise. “The number of organ-specific proteins is really small,” he says.

“I guess this means the human proteome project is basically done, and it didn’t take a billion dollars as people predicted,” says John R. Yates III, a proteomics expert at Scripps Research Institute California who was not involved with either study. “In general, the first 90% of projects like these is the easy part, and the last 10% is the really hard and expensive part.”

Pandey and Kuster both say their maps will remain drafts for the foreseeable future. “The proteome is dynamic. We always get a freeze-frame picture,” Pandey says. “We may never be able to claim completeness—and perhaps we don’t really have to,” Kuster says.

Congratulations to Akileseh, Bernhard and their teams for publishing draft “maps” of the human proteome in back-to-back Nature papers this week. In these seminal works the two groups independently assembled mass spectrometry evidence for at least one protein isoform of between 84-92% of known human proteins. In the same way that “maps” allow us to navigate through a multi-dimensional geographical reality, these publications produce tools that allow us to unravel the dynamic human proteome. The ongoing task will now be based upon the shoulders of many giants like the human genome, these new works and many publications assembled around the HUPO Human Proteome Project (HPP). Whilst the new studies represent a marvelous resource, raising many intriguing questions, they do however represent the tip of the HPP iceberg. Both works unambiguously demonstrate that the road to a complete Human Proteome will be far more difficult - with intricacies, challenges and deliverables beyond what were initially anticipated. Recognising this complexity, HUPO has predicted the journey will need: (i) full coverage of every expressed protein from the genome; (ii) analyses of the forms these proteins take; (iii) spatiotemporal cellular and tissue localisation data ; (iv) protein interaction data based upon structural biology; (v) understanding the biology of protein post-translational modifications, and (vi) detailed information about quantitation and roles in human health and disease. This journey desperately needs “maps” so that we can navigate the anticipated HPP complexity in a sustained, cooperative global effort where all systems biology and informatics scientists, academics, clinicians, instrument/ technology companies and biotech/pharmaceutical industries are engaged.